Effect of Micromixer Design on Lipid Nanocarriers Manufacturing for the Delivery of Proteins and Nucleic Acids.

Lipid-based nanocarriers have emerged as helpful tools to deliver sensible biomolecules such as proteins and oligonucleotides. To have a fast and robust microfluidic-based nanoparticle synthesis method, the setup of versatile equipment should allow for the rapid transfer to scale cost-effectively while ensuring tunable, precise and reproducible nanoparticle attributes. The present work aims to assess the effect of different micromixer geometries on the manufacturing of lipid nanocarriers taking into account the influence on the mixing efficiency by changing the fluid-fluid interface and indeed the mass transfer. Since the geometry of the adopted micromixer varies from those already published, a Design of Experiment (DoE) was necessary to identify the operating (total flow, flow rate ratio) and formulation (lipid concentration, lipid molar ratios) parameters affecting the nanocarrier quality. The suitable application of the platform was investigated by producing neutral, stealth and cationic liposomes, using DaunoXome®, Myocet®, Onivyde® and Onpattro® as the benchmark. The effect of condensing lipid (DOTAP, 3-10-20 mol%), coating lipids (DSPE-PEG550 and DSPE-PEG2000), as well as structural lipids (DSPC, eggPC) was pointed out. A very satisfactory encapsulation efficiency, always higher than 70%, was successfully obtained for model biomolecules (myoglobin, short and long nucleic acids).

Effects of cardiac rehabilitation on cardiopulmonary test parameters in heart failure: A real world experience.

Background: Cardio-Pulmonary Exercise Test (CPET) is the gold standard for evaluation of patients with heart failure (HF); however, its use is limited in everyday practice. We analyzed the use of CPET for HF management in the real world. Methods: From 2009 to 2022, 341 patients with HF underwent 12-16 weeks of rehabilitation in our Centre. We present data from 203 patients (60%), excluding those unable to perform CPET, those with anaemia and severe pulmonary disease. Before and after rehabilitation, we performed CPET, blood tests and echocardiography, tailoring individual physical training to the results of baseline test. The following variables were considered: peak Respiratory Equivalent Ratio (RER), peakVO2 (ml/Kg/min), VO2 at aerobic threshold (VO2AT,% maximal), VE/VCO2 slope, P(ET)CO2, VO2 /Work ratio (ΔVO2/ΔWork). Results: Rehabilitation improved peak VO2, pulse O2, VO2 AT and ΔVO2/ΔWork in all patients by about 13% (p < 0.01). Most patients (126, 62%) showed a reduced left ventricular ejection fraction (HFrEF), but rehabilitation was effective also in patients with mildly reduced (HFmrEF: n = 55, 27%) or preserved ejection fraction (HFpEF: n = 22, 11%). Conclusions: Rehabilitation in patients with heart failure induces a significant recovery of cardiorespiratory performance easily assessed by CPET, that is applicable to the majority of them and should be used routinely in the programming and evaluating of cardiac rehabilitation programs.

Graphene Nanoplatelets-Based Textured Polymeric Fibrous Fabrics for the Next-Generation Devices.

Graphene is a 2D crystal composed of carbon atoms in a hexagonal arrangement. From their isolation, graphene nanoplatelets (nCD) have revolutionized material science due to their unique properties, and, nowadays, there are countless applications, including drug delivery, biosensors, energy storage, and tissue engineering. Within this work, nCD were combined with PLA, a widely used and clinically relevant thermoplastic polymer, to produce advanced composite texturized electrospun fabric for the next-generation devices. The electrospinning manufacturing process was set-up by virtue of a proper characterization of the composite raw material and its solution. From the morphological point of view, the nCD addition permitted the reduction of the fiber diameter while the texture allowed more aligned fibers. After that, mechanical features of fabrics were tested at RT and upon heating (40 °C, 69 °C), showing the reinforcement action of nCD mainly in the texturized mats at 40 °C. Finally, mats' degradation in simulated physiological fluid was minimal up to 30 d, even if composite mats revealed excellent fluid-handling capability. Moreover, no toxic impurities and degradation products were pointed out during the incubation. This work gains insight on the effects of the combination of composite carbon-based material and texturized fibers to reach highly performing fabrics.

Improvement of functional capacity in sacubitril-valsartan treated patients assessed by cardiopulmonary exercise test.

Neprilisin and angiotensin receptor inhibition (Sacubitril/Valsartan, i.e. ARNI) is recommended in heart failure guidelines for patients in NYHA class II-III with reduced left ventricular ejection fraction (LVEF). ARNI increase survival and quality of life; due to their hemodynamic effects, ARNI could also affect exercise tolerance. We studied the effects of ARNI on cardiopulmonary test (CPET) after six months of treatment in 35 patients [67 ± 11 years; LVEF 31 ± 6%; NT-proBNP 1822 ± 1651 pg/ml; ICD/CRT since at least 6 months in 26/35], treated with increasing doses of Sacubitril/Valsartan up to 318 ± 36 mg/die. In addition, levels of NT-proBNP, renal function, electrolytes, and echocardiocolorDoppler were assessed in the same time periods. No variations of renal function and/or potassium levels were observed; NT-proBNP decreased. Most CPET variables were improved by ARNI (p < .05): peak VO2 and O2 pulse increased (from 15.8 ± 3.4 to 17.0 ± 4.0 ml/kg/min and from 11.5 ± 2.5 to 12.6 ± 2.4 ml/beat, respectively), while VEVCO2 slope decreased from 35.2 ± 11.2 to 33.1 ± 12.3. A significant relationship (p < .05) was observed between the amount of increase in LVEF and that of O2 pulse in all patients, and between the amount of decrease in PAPs and that of VEVCO2 slope in patients showing pulmonary hypertension in baseline. In a subgroup of 22 patients who already completed A 1 year follow-up, overall CPET improvement was maintained. In conclusion, already in the short term ARNI favourably affect cardiopulmonary response to exercise in heart failure patients; such a change seems to be preserved on a longer period.

[Safety and efficacy of early discharge and outpatient rehabilitation after myocardial infarction for low-risk patients]. / Sicurezza ed efficacia della dimissione precoce associata a riabilitazione ambulatoriale dopo infarto miocardico nel paziente a basso rischio.

BACKGROUND: Guidelines recommend early discharge and rehabilitation after ST-elevation myocardial infarction (STEMI) in low-risk patients. However, low risk is not established according to well-defined criteria and often it depends on subjective judgment. The aim of this real-life study is to confirm that early discharge is safe in patients at low risk according to selected criteria and subsequent outpatient rehabilitation is associated with clinical benefits. METHODS: Patients with STEMI treated with primary percutaneous coronary intervention from October 2010 to October 2017, identified as being at low risk (according to predefined criteria), discharged by day 5, were studied retrospectively. Basal characteristics and 30-day outcome were evaluated and a comparison was made between patients who completed or did not complete outpatient rehabilitation. RESULTS: We enrolled 193 STEMI patients treated with percutaneous coronary intervention for STEMI, early discharged and at low risk: 132 completed outpatient rehabilitation and 61 did not. The increase in cardiac enzymes and the occurrence of arrhythmias were the only independent predictors of completion of outpatient rehabilitation. After 30 days from discharge, adverse events were rare and not significantly different between groups. Optimal pharmacological therapy was achieved more often in the rehabilitation group (58.3% vs 44.3%; p<0.05). CONCLUSIONS: Early discharge within 5 days of STEMI has been proved feasible and safe in our population of well-defined low-risk patients. Early participation in a rehabilitation program was associated with a more adequate titration of therapy.

A brief period of intensive cardiac rehabilitation improves global longitudinal strain and diastolic function after a first uncomplicated myocardial infarction.

Objectives In patients with abnormal left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI), cardiac rehabilitation with physical training prevents cardiac remodelling. To define the role of rehabilitation in the recovery of ventricular function in less severe cases, we studied its effects on more refined indexes of left ventricular function in uncomplicated, low-risk patients. Methods and results Fifty-five patients underwent percutaneous coronary revascularization after uncomplicated first AMI. Thirty-four started cardiac rehabilitation with counselling and physical training; 21 patients did not train, followed a counselling program and were taken as controls. Echocardiography was performed at baseline, after rehabilitation or counselling program and at six months follow-up. We measured: global strain (GS%) with speckle tracking analysis, E/e' by tissue Doppler imaging (TDI), left ventricular elastance (KLV) from the deceleration time (DT), LVEF, systolic and diastolic volumes, wall motion score index (WMSI). At baseline, groups had similar GS%, KLV, LVEF, DT, E/e', systolic and diastolic volumes, WMSI. Rehabilitation increased peak VO2 by 18% (P < 0.05) and improved GS%, KLV, LVEF, E/e' and WMSI (P < 0.02) that were unchanged in controls. The improvement persisted at six months. Conclusions After a first uncomplicated AMI, abnormalities of left systolic and diastolic ventricular function may be present persisting over time despite a normal LVEF, which are fully reverted by cardiac rehabilitation.

Intermittent levosimendan infusions in advanced heart failure: a real world experience.

Objective To analyse the effects of levosimendan infusions in advanced heart failure. Methods Patients with advanced heart failure treated with repeated levosimendan infusions were retrospectively compared with controls. Clinical, blood and echocardiographic parameters were obtained at baseline and after 12 months, and before and after each levosimendan infusion. Hospitalizations for heart failure and in-hospital length of stay in the 6 months before enrolment and after 6 and 12 months were recorded, along with 1-year mortality. Results Twenty-five patients treated with levosimendan and 25 controls were studied. After each levosimendan infusion, ventricular function and various clinical and metabolic parameters were improved. After 12 months, left ventricular ejection fraction (LVEF) had improved compared with baseline in the levosimendan group. The 1-year mortality rate was similar in both groups. During the 6 months before enrolment, hospitalizations were fewer in controls compared with the levosimendan group; after 6 and 12 months they increased in controls and decreased in the levosimendan group. Seven patients were super-responders to levosimendan, with LVEF improving more than 20% and hospitalizations being reduced at 12 months compared with the rest of the levosimendan group. Conclusion Intermittent levosimendan improved LVEF and decreased hospitalizations in advanced heart failure and represents a therapeutic option for patients whose disease is worsening.

Lung ultrasound and transthoracic impedance for noninvasive evaluation of pulmonary congestion in heart failure.

BACKGROUND: In patients with heart failure, many indexes are available for noninvasive identification of pulmonary congestion: E/E' at echocardiography; plasma levels of brain natriuretic peptide (BNP) (pg/ml); number of B-lines at lung ultrasound; and transthoracic conductance [thoracic fluid content (TFC)TT = 1/Ω] at impedance cardiography (ICG). METHODS: We obtained 75 measures from 50 patients (72 ±â€Š10 years, NYHA 2.4 ±â€Š0.7, ejection fraction 31 ±â€Š7%), 25 of them studied before and after intravenous diuretics, in whom we assessed the following: E/e' from Doppler echocardiogram; BNP plasma levels; presence and number of B-lines at lung ultrasound; and TFCTT from ICG. We determined the relationship among these indexes and their change with treatment, and compared B-lines and TFC for the diagnosis of pulmonary congestion. Finally, we considered the timing and the personnel required for performing and interpreting each test. RESULTS: A mutual relationship was observed between all the variables. After clinical improvement, changes in each variable were of similar direction and magnitude. Congestion (estimated by chest radiograph) was present in 59% of the patients: TFC value and B-line number had the best sensitivity and specificity for its detection. BNP determination and ICG assessment were performed by a nurse (15 min), and echocardiography and lung ultrasound were performed by a cardiologist (15 min). CONCLUSION: The correlation between all indexes and their consensual change after improvement of the clinical status suggests that they all detect pulmonary congestion, and that using at least two indexes improves sensitivity and specificity. The choice among the methods may be determined by the patient characteristics or by the clinical setting.

Correlation between trans and intra-thoracic impedance and conductance in patients with chronic heart failure.

AIMS: In chronic heart failure, changes of intra-thoracic impedance (Z0IT) may suggest impending pulmonary congestion; a similar result has been found by measuring trans-thoracic conductance (TFCTT = 1/Z0 = 1/kΩ). We assumed that a relationship could exist between Z0IT and TFCTT. METHODS: We collected 140 measurements from 70 patients carrying an implantable cardioverter-defibrillator/cardiac resynchronization device with the CareLink function (71 ± 9 years, New York Heart Association (NYHA) 2.4 ± 0.9, ejection fraction 31 ± 8%, optimal treatment); they were studied during system alarms and after appropriate treatment (diuretics and/or vasodilators, n = 42) or during clinical stability and at the time of a system alarm (n = 28); correspondent BNP values were obtained. We related Z0IT obtained by the device, with TFCTT obtained with a commercial system. RESULTS: A strong relationship was found between Z0IT and TFCTT. Changes in the variables after treatment or during worsening conditions were of the same direction and order of magnitude, and were related to BNP levels obtained simultaneously. CONCLUSIONS: Trans-thoracic conductance, similarly to intra-thoracic impedance, may noninvasively point to pulmonary congestion and be useful in patients not carrying an implanted device. The possibility of remotely obtaining this variable should be evaluated for the telemonitoring of heart failure patients.

Pulmonary congestion at rest and abnormal ventilation during exercise in chronic systolic heart failure.

BACKGROUND: In patients with chronic heart failure, abnormal ventilation at cardiopulmonary testing (expressed by minute ventilation-to-carbon dioxide production, or VE/VCO2 slope, and resting end-tidal CO2 pressure) may derive either from abnormal autonomic or chemoreflex regulation or from lung dysfunction induced by pulmonary congestion. The latter hypothesis is supported by measurement of pulmonary capillary wedge pressure, which cannot be obtained routinely but may be estimated noninvasively by measuring transthoracic conductance (thoracic fluid content 1/kΩ) with impedance cardiography. METHODS AND RESULTS: Preliminarily, in 9 patients undergoing invasive hemodynamics during cardiopulmonary testing, we demonstrated a significant relationship between VE/VCO2 slope and resting end-tidal CO2 pressure with baseline and peak pulmonary capillary wedge pressure. Later, noninvasive hemodynamic evaluation by impedance cardiography was performed before cardiopulmonary testing in 190 patients with chronic systolic heart failure and normal lung function (aged 67±3 years, 71% with ischemia, ejection fraction 32±7%, 69% with implantable cardioverter-defibrillator or cardiac resynchronization therapy). In this group, we determined the relationship between abnormal ventilation (VE/VCO2 slope and resting end-tidal CO2 pressure) and transthoracic conductance. In the whole population, thoracic fluid content values were significantly related to VE/VCO2 slope (R=0.63, P<0.0001) and to resting end-tidal CO2 pressure (R=-0.44, P<0.001). CONCLUSIONS: In patients with chronic heart failure, abnormal ventilation during exercise may be related in part to pulmonary congestion, as detected by resting baseline impedance cardiography.

Prognostic value of noninvasive hemodynamic evaluation of the acute effect of levosimendan in advanced heart failure.

AIMS: Optimization of inotropic treatment in worsening heart failure sometimes requires invasive hemodynamic assessment in selected patients. Impedance cardiography (ICG) may be useful for a noninvasive hemodynamic evaluation. METHODS: ICG was performed in 40 patients (69 ± 8 years; left ventricular ejection fraction 27.5 ± 5.6%; New York Heart Association 3.18 ± 0.34; Interagency Registry for Mechanically Assisted Circulatory Support 5.48 ± 0.96, before and after infusion of Levosimendan (0.1­0.2 µg/kg per min for up to 24 h). Echocardiogram, ICG [measuring cardiac index (CI), total peripheral resistances (TPRs) and thoracic fluid content (TFC)] and plasma levels of brain natriuretic peptide (BNP) were obtained; in nine patients, right heart catheterization was also carried out. RESULTS: When right catheterization and ICG were performed simultaneously, a significant relationship was observed between values of CI and TPR, and between TFC and pulmonary wedge pressure. ICG detected the Levosimendan-induced recovery of the hemodynamic status, associated with improved systolic and diastolic function and reduction in BNP levels. One-year mortality was 4.4%. At multivariate analysis, independent predictors of mortality were: no improvement in the severity of mitral regurgitation, a persistent restrictive filling pattern (E/E' > 15), a reduction of BNP levels below 30% and a change below 10% in CI, TPR and TFC. When combined, absence of hemodynamic improvement at ICG could predict 1-year mortality with better sensitivity (86%) and specificity (85%) than the combination of echocardiographic and BNP criteria only (sensitivity 80% and specificity 36%). CONCLUSION: Noninvasive hemodynamic evaluation of heart failure patients during infusion of inodilator drugs is reliable and may help in their prognostic stratification.

Transthoracic bioimpedance and brain natriuretic peptide assessment for prognostic stratification of outpatients with chronic systolic heart failure.

BACKGROUND: In patients with chronic heart failure, physical evaluation and clinical judgment may be inadequate for prognostic stratification. HYPOTHESIS: Information obtained with simple bedside tests would be helpful in patient management. METHODS: We report on 142 outpatients with systolic heart failure seen at our heart failure unit from 2007 to 2010 (ages 69.4 ± 8.9 years; ejection fraction [EF] 30.6 ± 6.1%; 43% with implanted defibrillators and/or resynchronization devices). At their first visit, we assessed levels of brain natriuretic peptide (BNP) (pg/mL), evaluated transthoracic conductance (TFC) (1/kΩ) by transthoracic bioimpedance, and performed echocardiography. RESULTS: Four-year mortality was 21.2%. At multivariate analysis, surviving and deceased subjects did not differ regarding New York Heart Association, age, gender, heart failure etiology, or EF at index visit. Patients who died had higher BNP and TFC (BNP = 884 ± 119 pg/mL vs 334 ± 110 pg/mL; TFC = 50 ± 8/kΩ vs 37 ± 7/kΩ, both P < 0.001]. Patients with BNP < 450 pg/mL and TFC < 40/kΩ had a 2.1% 4-year mortality, compared to 46.5% mortality of patients having BNP ≥ 450 pg/mL and TFC ≥ 40/kΩ. BNP ≥ 450 pg/mL and TFC ≥ 40/kΩ showed high sensitivity (91%) and specificity (88%)in identifying patients who died at follow-up. CONCLUSIONS: The combined use of BNP and impedance cardiography during the first assessment of a patient in a heart failure unit identified those carrying a worse medium-term prognosis. This approach could help the subsequent management of patients, allowing better clinical and therapeutic strategies.

Effects of slow deep breathing at high altitude on oxygen saturation, pulmonary and systemic hemodynamics.

Slow deep breathing improves blood oxygenation (Sp(O2)) and affects hemodynamics in hypoxic patients. We investigated the ventilatory and hemodynamic effects of slow deep breathing in normal subjects at high altitude. We collected data in healthy lowlanders staying either at 4559 m for 2-3 days (Study A; N = 39) or at 5400 m for 12-16 days (Study B; N = 28). Study variables, including Sp(O2) and systemic and pulmonary arterial pressure, were assessed before, during and after 15 minutes of breathing at 6 breaths/min. At the end of slow breathing, an increase in Sp(O2) (Study A: from 80.2±7.7% to 89.5±8.2%; Study B: from 81.0±4.2% to 88.6±4.5; both p<0.001) and significant reductions in systemic and pulmonary arterial pressure occurred. This was associated with increased tidal volume and no changes in minute ventilation or pulmonary CO diffusion. Slow deep breathing improves ventilation efficiency for oxygen as shown by blood oxygenation increase, and it reduces systemic and pulmonary blood pressure at high altitude but does not change pulmonary gas diffusion.

Diastolic dysfunction and abnormal exercise ventilation predict adverse outcome in elderly patients with chronic systolic heart failure.

BACKGROUND: Heart failure is increasing in the elderly and represents a socioeconomic burden requiring the correct management for which risk stratification is mandatory. Among younger patients, echocardiogram and cardiopulmonary exercise test are useful in prognostic stratification. Few studies have analyzed the utility of these tests in elderly patients. METHODS: We report on 90 patients over 70 years old, on whom cardiopulmonary tests and echocardiograms were performed between 1998 and 2006 (67 M, 23 F; 75 ± 3 years; ejection fraction (EF) 30 ± 6%; NYHA 2.1 ± 0.8; 60% ischemic; therapy according to international guidelines). Echocardiographic variables were (1) left ventricular ejection fraction (EF); (2) severity of diastolic dysfunction on multiparametric examination of Doppler and TDI parameters; (3) severity of functional mitral regurgitation. Cardiopulmonary variables were (1) peak VO(2); (2) peak O(2) pulse; (3) peak respiratory quotient (RQ); (4) VE/VCO(2) slope. Endpoint considered was mortality of any cause at three-years follow-up. RESULTS: Mortality was 21%. At univariate analysis, survivors (n = 71) and deceased (n = 19) were similar for age, NYHA class, peakVO(2) and RQ; they differed for EF, severity of mitral regurgitation, severity of diastolic dysfunction, O(2) pulse and VE/VCO(2) slope. At multivariate analysis, only VE/VCO(2) slope and severe diastolic dysfunction (restrictive filling pattern) discriminated between the two groups. In particular, the association of restrictive filling pattern and VE/VCO(2) slope ≥ 45 predicted 3-year mortality with sensitivity of 84% and specificity of 88%. CONCLUSIONS: Echocardiographic and cardiopulmonary data can identify high-risk elderly patients with systolic heart failure, who may need aggressive clinical management.

Effects of selective and nonselective beta-blockade on 24-h ambulatory blood pressure under hypobaric hypoxia at altitude.

BACKGROUND: Little is known about the effects of cardiovascular drugs at high altitude. OBJECTIVE: To assess 24-h blood pressure (BP) and heart rate (HR) during short-term altitude exposure in healthy normotensive persons treated with carvedilol or nebivolol. METHODS: Participants were randomized in double-blind to placebo, nebivolol 5 mg once daily or carvedilol 25 mg b.i.d. Tests were performed at sea level (baseline and after 2 weeks treatment) and on second to third day at altitude (Monte Rosa, 4559 m), still on treatment. Data collection included conventional BP, 24-h ambulatory BP monitoring (ABPM), oxygen saturation (SpO2), Lake Louise Score and adverse symptoms score. RESULTS: Twenty-four participants had complete data (36.4 ± 12.8 years, 14 men). Both beta-blockers reduced 24-h BP at sea level. At altitude 24-h BP increased in all groups, mainly due to increased night-time BP. Twenty-four-hour SBP at altitude was lower with carvedilol (116.4 ± 2.1 mmHg) than with placebo (125.8 ± 2.2 mmHg; P < 0.05) and intermediate with nebivolol (120.7 ± 2.1 mmHg; NS vs. others). Rate of nondipping increased at altitude and was lower with nebivolol than with placebo (33 vs. 71%; P = 0.065). Side effects score was higher with carvedilol than with placebo (P = 0.04), and intermediate with nebivolol. SpO2 at altitude was higher with placebo (86.1 ± 1.2%) than with nebivolol (81.7 ± 1.1%; P = 0.07) or carvedilol (81.1 ± 1.1%; P = 0.04). CONCLUSIONS: Both carvedilol and nebivolol partly counteract the increase in BP at altitude in healthy normotensive individuals but are associated with a lower SpO2. Carvedilol seems more potent in this regard, whereas nebivolol more effectively prevents the shift to a nondipping BP profile and is better tolerated.

Effectiveness of barnidipine 10 or 20 mg plus losartan 50-mg combination versus losartan 100-mg monotherapy in patients with essential hypertension not controlled by losartan 50-mg monotherapy: A 12-week, multicenter, randomized, open-label, parallel-group study.

BACKGROUND: Increasing the dose or adding a second antihypertensive agent are 2 possible therapeutic choices when blood pressure (BP) is poorly controlled with monotherapy. OBJECTIVE: This study investigated the effectiveness and tolerability of barnidipine 10 or 20 mg added to losartan 50 mg versus losartan 100 mg alone in patients with mild to moderate essential hypertension whose BP was uncontrolled by losartan 50-mg monotherapy. METHODS: This was a 12-week, multicenter, randomized, open-label, parallel-group study. Eligible patients (aged 30-74 years) had uncontrolled hypertension, defined as office sitting diastolic BP (DBP) > or =90 mm Hg and/or systolic BP (SBP) > or =140 mm Hg, and mean daytime DBP > or =85 mm Hg and/or SBP > or =135 mm Hg. All were being treated with losartan 50 mg at enrollment. After a 1-week run-in period while taking losartan 50 mg, patients were randomly assigned to 6 weeks of treatment with open-label barnidipine 10 mg plus losartan 50 mg or losartan 100-mg monotherapy. At the end of this period, patients with uncontrolled BP had barnidipine doubled to 20 mg and continued for an additional 6 weeks, whereas patients not achieving control on treatment with losartan 100 mg were discontinued. Office BP was measured at each visit, whereas 24-hour ambulatory BP monitoring (ABPM) was performed at randomization and at the final visit (ie, after 12 weeks of treatment, or at 6 weeks for patients not controlled on losartan 100 mg). The intent-to-treat population included all randomized patients who received at least one dose of study treatment and had valid ABPM recordings at baseline and the final visit. The primary end point was the change in daytime DBP between baseline and 12 weeks of treatment, compared between the combination treatment and monotherapy. Adverse events (AEs) were evaluated during each study visit. RESULTS: A total of 93 patients were enrolled (age range, 30-75 years; 60% [56/93] men). After the 1-week run-in period, 68 patients were randomly assigned to 6 weeks of treatment with open-label barnidipine 10 mg plus losartan 50 mg (n = 34) or losartan 100-mg monotherapy (n = 34). A total of 53 patients were evaluable (barnidipine plus losartan, n = 28; losartan, n = 25). After 6 weeks of treatment, 18 patients in the combination treatment group (64.3%) had their dose of barnidipine doubled from 10 to 20 mg because BP was not normalized by treatment, whereas 8 patients in the losartan group (32.0%) were discontinued for the same reason. The between-treatment difference (losartan alone - combination treatment) for changes from baseline in daytime DBP was -1.7 mm Hg (95% CI, -5.8 to 2.4 mm Hg; P = NS). A similar result was observed for daytime SBP (-3.2 mm Hg; 95% CI, -8.1 to 1.7 mm Hg; P = NS). Likewise, no significant differences were found for nighttime values (mean [95% CI] DBP, 0.5 mm Hg [-3.7 to 4.7 mm Hg]; SBP, 1.5 mm Hg [-4.1 to 7.1 mm Hg]) or 24-hour values (DBP, -0.9 mm Hg [-4.8 to 2.9 mm Hg]; SBP, -1.6 mm Hg [-5.9 to 2.7 mm Hg]). Combination treatment was associated with a significantly higher rate of SBP responder patients (ie, <140 mm Hg or a reduction of > or =20 mm Hg) compared with monotherapy (82.1% [23/28] vs 56.0% [14/25]; P = 0.044). Drug-related AEs were reported in 4 patients taking combination treatment (total of 7 AEs, including 2 cases of peripheral edema and 1 each of tachycardia, atrial flutter, tinnitus, confusion, and polyuria) and in 2 patients taking losartan alone (total of 2 AEs, both tachycardia). CONCLUSIONS: This open-label, parallel-group study found that there was no significant difference in the BP-lowering effect of barnidipine 10 or 20 mg in combination with losartan 50 mg compared with losartan 100-mg monotherapy in these patients with essential hypertension previously uncontrolled by losartan 50-mg monotherapy. However, the percentage of responders for SBP was significantly higher with the combination. Both treatments were generally well tolerated. European Union Drug Regulating Authorities Clinical Trials (EudraCT) no. 2006-001469-41.

Acute effects of levosimendan on mitral regurgitation and diastolic function in patients with advanced chronic heart failure.

BACKGROUND: We analyzed the inodilator properties of levosimendan in patients with chronic heart failure and severe functional mitral regurgitation. METHODS: We studied 20 patients under optimal treatment and in stable clinical condition (New York Heart Association 3.19 + or - 0.66; 70 + or - 7 years). Levosimendan was infused as a bolus (12 microg/kg in 10 min) followed by a 24-h infusion (0.1-0.2 microg/kg per min). Before and after infusion, Doppler echocardiography, brain natriuretic peptide determination and noninvasive hemodynamic monitoring with bioimpedance cardiography were performed. RESULTS: Levosimendan improved left ventricular ejection fraction (ejection fraction 31 + or - 4 from 27 + or - 4, P < 0.05), decreased brain natriuretic peptide (333 + or - 139 from 629 + or - 63 pg/ml, P < 0.01), reduced mitral valve effective regurgitant orifice area to 27 + or - 5 from 36 + or - 7 mm (P < 0.01) and the velocity of displacement of mitral annulus [ratio between E and E' waves on Doppler and tissue Doppler (E/E') from 22.7 + or - 1.6 to 13.1 + or - 0.6, P < 0.01]. Noninvasive hemodynamic monitoring showed increased acceleration index (a marker of inotropism), and reduced peripheral resistances and thoracic fluid content (P < 0.01). After 4 weeks of washout, some of these effects were still evident. CONCLUSION: In patients with chronic heart failure and functional mitral regurgitation, levosimendan acutely improved systolic and diastolic function, reduced mitral regurgitation and modulated neurohormonal activation, with a tendency for these changes to persist over a short-term follow-up.

Transthoracic bioimpedance and brain natriuretic peptide levels accurately indicate additional diastolic dysfunction in patients with chronic advanced systolic heart failure.

AIMS: Diastolic dysfunction in patients with heart failure has prognostic relevance, possibly because of its relationship with worsening haemodynamic status. In the quest for simpler indexes of haemodynamic status in patients, brain natriuretic peptide (BNP) levels have been proposed as a surrogate of diastolic function. To date, the value of combining BNP levels with non-invasive haemodynamic monitoring by transthoracic electric bioimpedance (TEB) for the prediction of diastolic function has not been evaluated. METHODS AND RESULTS: We compared left ventricular diastolic function measured by tissue Doppler imaging (TDI) with TEB results and BNP levels in 120 patients with chronic advanced systolic heart failure on optimal treatment (70 +/- 9 years, NYHA 2.4 +/- 0.8, ejection fraction 31 +/- 5%). Of the TEB variables measured, we only considered thoracic fluid content (TFC). To describe diastolic function, we used the TDI of the velocity of displacement of the mitral annulus (E') and the ratio E/E'. In all patients, E/E' was significantly related to TFC and to BNP levels (P < 0.001). Moreover, the combination of BNP > or = 350 pg/mL and TFC > or = 35/kOmega identified patients with diastolic dysfunction (defined as E/E' > or = 15) with high sensitivity and specificity (95 and 94%, respectively). CONCLUSION: The combination of transthoracic bioimpedance monitoring and BNP measurement accurately indicated the presence of diastolic dysfunction in most patients. These user-friendly and operator-independent tools may be useful as a screening assessment for diastolic dysfunction, and consequently abnormal central haemodynamic status, either in ambulatory patients or when an adequate echocardiographic evaluation is not readily available.

Device-guided paced breathing in the home setting: effects on exercise capacity, pulmonary and ventricular function in patients with chronic heart failure: a pilot study.

BACKGROUND: Regular slow breathing is known to improve autonomic cardiac regulation and reduce chemoreflex sensitivity in heart failure. We explored the acceptability and usefulness of a device for paced slow breathing at the home setting. METHODS AND RESULTS: In this open pilot study, 24 patients with chronic heart failure (61% males, mean age, 64+/-9 years; New York Heart Association class, 2.81+/-0.01) were randomized to a control group receiving conventional treatment (n=12) or to a group receiving conventional treatment and device-guided paced breathing (n=12). Groups were comparable for age, therapies, and clinical characteristics. They were evaluated at baseline and again after 10 weeks by Doppler echocardiography, pulmonary function, cardiopulmonary stress test, and quality of life (Minnesota Quality of Life questionnaire). The treatment group was instructed to use the equipment for 18 minutes twice daily. The device is a computerized box connected to a belt-type respiration sensor and to headphones; it generates musical tones (based on the user's breathing rate and inspiration ratio), which guide the user to progressively and effortlessly slow his or her breathing rate <10 breaths/min. The treatment group showed high compliance to the device (90% of the prescribed sessions were completed). Blinded analysis of data demonstrated increased ejection fraction and decreased estimated pulmonary pressure in the echocardiograms of the treated group versus controls and favorable changes in New York Heart Association class, Ve/Vco(2), FEV(1), and a quality of life measure, as well (all P<0.05). CONCLUSIONS: This pilot investigation demonstrates that device-guided paced breathing at home is feasible and results in an improvement in clinically relevant parameters for patients with heart failure and systolic dysfunction.